14-hydroxymorphinan derivatives

ABSTRACT

N - SUBSTITUTED - 14 - HYDROXY-3-SUBSTITUTED-MORPHINAN DERIVATIVES HAVE BEEN FOUND TO POSSESS POTENT NARCOTIC AGONIST OR ANTAGONIST ACTIVITY. IN PARTICULAR, THE COMPOUND 3,14 - DIHYDROXY-N-CYCLOPROPYLMETHYLMORPHINAN HAS BEEN FOUND TO POSSESS POTENT NARCOTIC ANTAGONIST ACTIVITY. THESE COMPOUNDS ARE PREPARED BY TOTAL SYNTHESIS AND ARE NOT DERIVED FROM OPIUM ALKALOIDS.

United States Patent 3,819,635 14-HYDROXYMORPHINAN DERIVATIVES Irwin J. Pachter, Fayetteville, N.Y., and Bernard R. Belleau, Westmont, Quebec, and Ivo Monkovic, Candiac, Quebec, Canada, assignors to Bristol-Myers Company, New York, NY.

No Drawing. Continuation-impart of abandoned application Ser. No. 178,837, Sept. 8, 1971. This application Jan. 13, 1972, Ser. No. 217,633

Int. Cl. C07d 43/28 US. Cl. 260285 16 Claims ABSTRACT OF THE DISCLOSURE N substituted 14 hydroxy-B-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound 3,14 dihydroXy-N-cyclopropylmethylmorphinan has been found to possess potent narcotic antagonist activity. These compounds are prepared by total synthesis and are not derived from opium alkaloids.

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of a copending application, Ser. No. 178,837, filed Sept. 8, 1971, now abandoned.

BACKGROUND OF THE INVENTION (1) Field of the invention This invention embodies new and novel compounds useful as analgesics and/or narcotic antagonists and a new and novel total synthesis for their preparation.

(2) Description of the prior art (A) )-14 hydroXy-3-methoxy-N-methylmorphinan and derivatives thereof have been described by Y. K. Sawa and H. Tada in Tetrahedron, 24, pp. 6185-6196. This paper reports the compound 14-hydroxy-3-methoxy- N-methylmorphinan as being prepared from 14-hydroxydehydrothebainone, an opium alkaloid.

(B) US Pat. No. 3,166,559 disclosed compounds having the generic formula in which R represents a hydrogen atom or a (lower)alkyl group (e.g., methyl, ethyl, propyl), R represents a hydrogen atom, an aryloXy group (e.g., phenyloxy, naphthyloxy) or a substituted phenyloxy, substituted naphthyloxy wherein the substituent is (lower)alkyl (e.g., methyl, ethyl, propyl), (lower)alkoxy, (e.g., methoxy, ethoxy, propoxy), nitro or amino, X represents a hydrogen atom or a hydroxyl group and, in Formula I, one or two double bond(s) exist(s) in the C ring.

3,819,635 Patented June 25, 1974 Ice (C) British Pat. No. 1,028,407 discloses compounds having the generic formula wherein R represents an alkyl group having not more than five carbon atoms (e.g., methyl, ethyl, propyl), R represents a hydrogen atom or an aryloxy group (e.g., phenyloxy or naphthyloxy), R" represents a methylene group, a carbonyl group or a ketalated carbonyl .group (e.g., ethylenedioxymethylene or diethoxymethylene), X represents a hydrogen atom or hydroxyl group and Y represents an alkyl group having not more than five carbon atoms (e.g., methyl, ethyl or propyl), an aryl group (e.g., phenyl or naphthyl) or an aralkyl group in which the alkyl moiety has not more than five carbon atoms (e.g., benzyl or phenethyl) and shows various pharmacological activities such as analgesic activity, antitussive activity and anti-inflammatory activity.

SUMMARY OF THE INVENTION Compounds having the formula wherein R is selected from the group comprising and (lower) alkenyl in which R is H or CH R is selected from the group comprising 0 o i and Ji-om-Q,

R is H, (lower)acyl, trichloroacetyl or cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof are analgetic agents, narcoatic antagonists or intermediates in the preparation of such agents.

DISCLOSURE OF THE INVENTION This invention relates to the total synthesis of new and novel N-substituted-14hydroxy-3-substituted morphinan derivatives having the formula wherein R is selected from the group comprising /CH: --CHz-CECH, CH:CH=CH2, -CHz-CH=C\ and (lower)alkenyl in which R is H or CH R is selected from the group comprising R is H, (lower)acyl, trichloroacetyl or cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.

Drug abuse by thrill-seeking youth or by people looking for an escape from the realities of every day life has become more and more common place in our present society. One class of widely abused drugs are the narcotic analgetics such as codiene, morphine, meperidine, etc. It is because of the high addictive potential of these agents that much time and money are being expended by the pharmaceutical industry and by governments to try and discover and develop new non-addicting analgetics and/ or nareoatic antagonists.

It was therefore an object of the present invention to find new and novel compounds that had these characteristics.

It was further an object of the present invention to develop a method of synthesis that would not be dependent upon opium alkaloids as starting materials and yet would be commercially feasible.

The objectives of the present invention have been achieved by the provision of the compounds of formula I and by their total synthesis from the readily available starting material 7-methoxy-3,4-dihydro-1 [2H] -naphthalenone.

The compounds of the instant invention have the basic morphinan nucleus which is numbered and represented by the following plane formula:

Although there are three asymmetric carbons (asterisks) in the morphinan molecule, only two diastereoisomeric (racemic) forms are possible, because the iminoethano system, attached to position 9 and 13, is geometrically contained to a cis-(1,3-diaxial)-fusi0n. These racemates can therefore differ only at the junction of rings B and Cin other Words, in the configuration of carbon 14. The only variable will be the cis and trans relationship between the 5 (13) and 8 (14) bonds (Analgetics, Ed. George de Stevens, Academic Press, New York, p. 137 (1965 When in the compounds of the present invention, the 5 (l3) and 8 (14) bonds are trans to each other, we have compounds commonly desigated as isomorphinans. On the other hand, when 5 (13) and 8 (14) are cis to each other, we have compounds commonly desigated as morphinans. The use of a graphic representation of a morphinan or isomorphinan is meant to include the dl racemic mixture and the resolved d and l isomers thereof.

The isomorphinans disclosed and claimed herein are primarily useful as intermediates in the preparation of the biologically potent analgetic and/or narcotic antagonist agent of the present invention.

In addition, the isomorphinan and morphinan compounds of the present invention can exist as two optical isomers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphically illustrated as:

M ORPHINANS 2 on em:

ISOMORPHINANS and The present invention embodies all of the isomorphinan and morphinan isomers including the optical isomers in their resolved form. Those isomers which do not possess the desired biological activity can be transformed chemically into the desired product.

The optical isomers can be separated and isolated by fractional crystallization of the diastereoisomeric salts formed, for instance, with dor l-tartaric acid or D-(+)- u-bromocamphor sulfonic acid. The levorotatory isomers of the compounds of the present invention are the most preferred embodiments.

For the purpose of this disclosure, the term (lower) alkyl is defined as an alkyl radical containing 1 to 6 carbon atoms. (Lower)alkenyl is defined as a hydrocarbon radical of 3 to 7 carbons containing one double bond. The term (lower)acyl is an acyl radical of 2 to 6 carbon atoms, e.g., acetyl, propionyl, isobutyryl, etc. The term pharmaceutically acceptable acid addition salt is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts are commonly used to produce nontoxic salts of medicinal agents containing amine functions. Illustrative examples would be those salts formed by mixing the compounds of formula I with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric or tartaric, pamoic, lauric, stearic, palmitic, Oleic, myristic, lauryl sulfuric, naphthalinesulfonic, linoleic or linolenic acid, and the like.

The compounds of the instant invention are prepared by a total synthesis comprising at least 12 steps. Surprisingly, the synthesis is eificient and appears commercially feasible. The process is outlined in charts I, II, III and IV.

CHART I CH CE 0 3 1e 3 ii I II k can g E 1 3 110 xam e .6 H0 N P. v 2

vacc ne *2 CH 0 OH 0 Example 5 a VI v M6028 Exam 1e 7 4502M VII VIII CHART II 410 B?! N-CO E'G CF 0 Exam 1e (31 0 VIII X n-co ne a 03 Example 11 Oh o Example 15; C330 6 x 81 V XVI on 5 mmiz cm g g XVII xvnr xxx CHART III oil on Example 23; H

o a u a:

H0 33 Example 25; (31 0 XXV xxv:

New 6 mm mm a 1 NM on no XXIX CHART IV XXIII Exa 1e 32 xxxm XXXV

XXXVI XXXVI: ...4

A preferred embodiment of the present invention is the compounds having the formula XXXVI! and C3' 7 alkenyl in which R is H or CH R is selected from the group comprising II N onto-c111 -omo-, and l! 0,

R is selected from the group comprising H, (lower)acyl, trichloroacetyl and cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment is the compounds having the formula XXXXI wherein R is selected from the group comprising /CH3 -oH,-o cH, CH;CH=CH;, -CH;-CH=C 8 and C alkenyl in which R is H or CH R is selected from the group comprising 0 ll ower) alkyl, (lower) acyl, N C, I

and R is selected from the group comprising H, (lower) acyl, trichloroacetyl and cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.

A more preferred embodiment is the compounds of formula XXXXI wherein R is /CH3 CH2C CH, -CHz-CH=CH;, CIh-CH=C R cmQ-m or CH;-@

in which R is H or CH R is and R is H, (lower)acyl, trichloroacetyl or cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.

Another more preferred embodiment is the compounds of formula XXXXI where R is R is 0 l H, CH3. or CH;

and R is H; or a pharmaceutically acceptable acid addition salt thereof.

Most preferred embodiments are: (1) The compounds of formula XXXXI wherein R is H, R is and R is H; or the hydrochloride salt thereof.

(2) The compound of formula XXXXI wherein R is and R is H; or the hydrochloride salt thereof.

A preferred embodiment of the present inventionis the compounds having the formula 9 wherein R is H or (lower)alkyl, R is H,

in which R is H or CH More preferred embodiments are:

(1) The compound of formula XXXXII wherein R is CH and R is H.

(2) The compounds of formula XXXXI wherein R is CH, and R is COCF or CO Et.

(3) The compounds of formula XXXXII wherein R is CH and R is Also a preferred embodiment of the present invention is the compounds having the formula XXXXIII wherein R is H or (lower)alkyl and R is More preferred embodiments are:

(1) The compounds of formula XXXXIII wherein R is CH and R is (2) The compounds of formula XXXXIII wherein R is hydrogen and Still another preferred embodiment is the compounds having the formula xxxxtv wherein R is H of (lower)alkyl; or an acid addition salt thereof (preferably the hydrochloride or oxalate).

A more preferred embodiment is the compound of formula XXXXIV wherein R' is (3H or the oxalate salt thereof.

The processes for the preparation of the compounds of the instant invention are new and novel and also constitute preferred embodiments. Heretofore compounds of this type could only be prepared from opium alkaloids.

A preferred embodiment of the present invention is the process of preparing compounds having the formula 10 wherein R is selected from the group comprising -oH,-ozoH, -CH2CH:CH1, CHz-CH=C CHa and C alkenyl in which R is H or CH which process comprises the consecutive steps of (A) Treating the compound having the formula XKXXIIIa in which R is (lower)alkyl, with an alkylating or acylating agent having the formula X(Z)W in which W is a radical selected from the group comprisand C alkenyl in which R is H or CH Z is carbonyl and X is chloro, bromo or iodo, in an inert organic solvent in the presence of an organic tertiary amine to produce the compound having the formula in which R", Z and W are as defined above;

(B) Treating compound XXXXIIIb with lithium aluminum hydride where (Z) is carbonyl (ill).

in an inert organic solvent, to produce the compound having the formula no OH XXXXIa wherein R is selected from the group comprising CH3 CH1CECH, CH1CH=CH2, CH;-CH=C/ CH1CH=CH,

and C alkenyl; which process comprises the consecutive steps of (A) Treating the compound having the formula in which R is (lower)alkyl with an alkylating agent having the formula XXXXIIIb in which R and R are as above; and

(B) Cleaving the ether function of compound XXXXHIb by treatment with boron tribromide or pyridine hydrochloride.

More preferred embodiments are the process for the preparation compounds of formula XXXXIa wherein:

(1) In step (A) R' is methyl, the inert organic solvent is methylene chloride, dichloroethane or a (lower)alkanol, the organic tertiary amine is pyridine or triethylamine and the reaction is conducted at about 15 C. to about reflux temperature.

(2) In step (A) the organic solvent is methanol, ethanol, n-propanol or isopropanol, the tertiary amine is triethylamine and the reaction is conducted at about reflux temperature for about 5 to about 20 hours.

Another preferred embodiment of the present invention is the process for the preparation of compounds having the formula in which R is (lower)alkyl, which process comprises the consecutive steps of (A) Dehydrating the compound having the formula 10 N-CO R VIIIa in which R and R are (lower)alkyl, with a dehydrating agent to produce a compound having the formula n-co a in which R and R are as above; and

(B) Hydrolyzing compound Xa by treatment with an alkali metal hydroxide in a high boiling alkanol of Cs-CIZ carbons at about reflux temperature.

A more preferred embodiment is the process for the preparation of compounds of formula XXXXIIa wherein in step (A) the dehydrating agent is selected from the group comprising POCl P 0 thionyl chloride or KHSO in a tertiary amine selected from the group comprising pyridine, n-methylpiperidine, triethylamine and N,N-di-methylaniline, in the temperature range of about 15 C. to about 40 C., R is CH and in step (B) the hydroxide is sodium or potassium hydroxide.

A most preferred embodiment is the process for the preparation of compound of formula XXXXIIa wherein in step (A) R is methyl, the dehydrating agent is P001 the tertairy amine is pyridine, the temperature is about 20-25 C.; and in step (B) the hydroxide is potassium hydroxide.

Another preferred embodiment of the present invention is the process for the preparation of compounds having the formula XXXXIIIa which process comprises the consecutive steps of (A) Treating the compound having the formula N' COCF in which R is as above;

(B) Epoxidizing compound XXA with a perbenzoic acid in an inert organic solvent at about 10 C. to 40 C. to produce the compound having the formula ir-cocr' R 0 q XXIa in which R is as above;

in which R is (lower)alkyl;

(D) Treating compound XXIIa With lithium aluminum hydride at elevated temperatures in an inert organic solvent to produce the compound having the formula XXIIIa in which R is (lower)alkyl; and

(E) Cleaving the ether function of compound XXIIIa by treatment with pyridine hydrochloride at elevated temperatures.

A more preferred embodiment is the process of preparing compounds of formula XXXXIIIa wherein in step (A) the acylating agent is trifluoroacetic anhydride, the inert organic solvent is ether, dioxane or tetrahydrofuran; in step (B) the perbenzoic acid is m-chloroperbenzoic acid which is employed in about a 10% molar excess, in methylene chloride or dichloroethane at about room temperature; in step (C) the (lower)alkanol is methanol, ethanol, n-propanol or isopropanol at about reflux temperature for about 3 to 10 minutes; in step (0) the organic solvent is ether, dioxane or tetrahydrofuran, at about reflux temperatures for 10 to 60 minutes; and in step (E) at about 170200 C. for about 1 hour.

A most preferred embodiment is the process of preparing compounds of formula XXXXIIIa wherein in step (A) the acylating agent is trifluoroacetic anhydride, the solvent is dry ether; in step (B) m-chloroperbenzoic acid is employed in 10% excess in methylene chloride at about room temperature; in step (C) the alkanol is absolute ethanol at reflux tempenature for 5 minutes; in step (D) the solvent is tetrahydrofuran at about reflux temperature for about 15 minutes, and in step (E) the temperature is about 185-195 C. for about 1 hour.

Another preferred embodiment is the process for the preparation of compounds having the formula XXIIIa.

which process comprises the consecutive steps of (A) Dehydrating the compound having the formula VIIIa which R and R are as above;

14 (B) Hydrolyzing compound Xa by treatment with an alkali metal hydroxide in a high boiling alcohol of 05-012 carbons at about reflux temperature to produce the compound having the formula XXXXIIa.

in which R is (lower)alkyl;

(C) Treating compound XXXXIIa with trifluoroacetic anhydride or trifluoroacetyl halide wherein the halide is chloro, bromo or iodo in an inert organic solvent to produce the compound having the formula XXa.

in which R is as above,

(D) Epoxtdizing compound XXa with a perbenzoic acid in an inert organic solvent at about 10 C. to 40 C. to produce the compound having the formula wit-C005;

XXIB.

in which R is as above;

(E) Deacylatzng compound XXIa by treatment with sodium borohydride in a (lower)alkanol to produce the compound having the formula in which R is (lower)alkyl;

(F) Treating compound XXXIIa With lithium aluminum hydride at elevated temperatures in an inert organic solvent to produce the compound having the formula XXIIIa.

or potassium hydroxide; in step (C) the acylating agent is trifiuoroacetic anhydride, the inert organic solvent is ether, dioxane or tetrahydrofuran; in step (D) the perbenzoic acid is m-chloroperbenzoie acid which is employed in about a 10% molar excess, in methylene chloride or dichloroethane, at about room temperature; in step (E) the (lower)alkanol is methanol, ethanol, n-propanol or isopropanol at about reflux temperature for about 3 to 10 minutes; in step (F) the organic solvent is ether, dioxane or tetrahydrofuran, at about reflux tem- 15 peratures, for 10 to 60 minutes; and in step (G) the temperature is about l70-200 C. for about 1 hour.

A most preferred embodiment of the present invention is the process for preparing compounds of formula XXIIIa wherein in step (A) R is methyl, the dehydrating agent is PCl the tertiary amine is pyridine and the temperature is about 20-25 C.; in step (B) the hydroxide is potassium hydroxide; in step (C) the acylating agent is trifluoroacetic anhydride, the solvent is dry ether; in step (D) rn-chloroperbenzoic acid is employed in excess in methylene chloride at about room temperature; in step (E) the alkanol is absolute ethanol at reflux temperature for 5 minutes; in step (F) the solvent is tetrahydrofuran at about reflux temperature for about minutes; and in step (G) the temperature is about 185-195 C. for about 1 hour.

All of the compounds of the preferred embodiments herein are novel and valuable for this properties as analgesic and/or narcotic antagonist agents, or as intermediates in the preparation of compounds having these biological activities.

In particular, the compounds having the formula XXXXI are those which possess the most desirable properties; i.e., analgesic and/or narcotic antagonist properties. Some of the isomorphinan compounds of formula XXXX also have some biological activity, i.e., antitussive, mild analgetic, etc., activity, but their primary usefulness is in the preparation of compounds having the formula XXXXI It is well known in the narcotic analgesic prior art that it is possible for some compounds to possess both agonist and antagonist properties. An agonist is a compound that imitates a narcotic analgesic and possesses analgetic qualities. An antagonist is a compound that counteracts the analgetic and euphoric properties of a narcotic analgetic. It is possible for a compound to have both properties. A good example of such a compound is cyclazocine.

In vivo testing was conducted on the hydrochloride salts of compounds XD(, XXVII, XIXa, XIXb and XXIX, to determine their agonist and/or antagonist properties. Table V represents the results of the experiments. The figures reported are the number of milligrams/kilogram of body weight of compound that produced an agonist or antagonist effect in 50% of the mice and rats so tested adult humans is about 0.25 to 10 mg. three to four times a day. Orally the dose is in the range of about 2 to 50 mg. three or four times a day.

It has been reported in the literature that the compound haloperidol, 4- [4- (p-chlorophenyl -4-hydroxypiperidino] 4-fluorobutyrophenone (Merck Index, 8th edition, p. 515) has found some experimental use in the alleviation of narcotic addiction withdrawal symptoms. It is therefore a preferred embodiment of the present invention to combine haloperidol with the narcotic antagonists of the instant invention, particularly l-3,14-dihydroxy-6-cyclopropylmethylmorphinan, to produce a product not only preventing narcotic abuse, but at the same time providing supportive therapy in the absence of opiates.

Haloperidol is commonly administered orally in 0.5 to 5.0 mg. two or three times daily depending upon the severity of the illness. A dose of haloperidol in this range would be administered contemporaneously with an effective dose of the narcotic antagonist to produce the desired result.

Other combinations would include the narcotic antagonists in. combination with anti-anxiety agents such as chlorodiazepoxide and diazeparn, or phenathiazines like chlorpromazine, primazine or methotrimeprazine.

EXPERIMENTAL SECTION Example 1 3,4-dihydro-7-methoxy 2,2 tetramethylene 1(2H)- naphthalenone (II).A nitrogen atmosphere Was maintained throughout the following reaction. To a stirred and refluxing suspension of 12 g. (0.5 mole) of sodium hydride in 100 ml. of dry benzene was added during 30 minutes, 16.6 g. (0.2 mole) of anhydrous t-amyl alcohol. The reaction mixture was stirred and refluxed during 15 minutes,

( so)- and then a solution of 35.2 g. (0.2 mole) of 7-methoxy-3,

TABLE V ED e/ g.)

Agonist activity Antagonist activity Mouse phenyl- Oxymorphoue Oxymorphone Morphine antagoquinone writhing l straub tail 2 narcosis 3 nist rat tail flick 4 Test compound S.e. P.o. S.c. P.o. S.e. P.o. S.e. P.o.

XIX 5 E5 22 0. 44 15 0. 15 E0. 75 XIXa B 9 0.21 10 0. O2 0. 2 XIXI) E40 740 XXVII. 0. 045 16 3. 0 256 0. 4 XXIX 19 2180 1.0 64 0.15 Pentazocine 5. 2 64 18 210 15 N alorphiue. 0. 8 17 1. 25 128 0. Levallorphan 5 E15 0. 5 48 0. 2 cyclazocine.. 0. 041 4. 1 1 29 0. 12 Naloxone 40 0.22 15 0. 04

1 A 50 percent reduction in number of phenylquinone induced writhings [Siegmund, E. A., et al., Proc.

Biol. & Med, 95, p. 729 (1957)].

2 Antagonism of Straub Tail induced by oxymorplione (2 mg./kg., 3.0.) in 50 percent of mice.

8 Antagonism of righting reflex loss induced by oxymorphone (1.5 mg./kg., s.c.) in 50 percent of rats.

A 50 percent reduction of analgesic efiect induced by morphine (15 mg./kg., 5.0.) as measured by the rat tail iliek procedure. [Harris L. S., and Person, A. K., J. Pharmacol. & Exptl. Therap. 143, p. 141, (1964)].

5 Poorly defined dose response.

8 Poorly defined.

It is apparent from the testing that compounds XIX, XIXa and XXIX have weak subcutaneous analgesic activity but are relatively potent parenteral antagonists. At the same time, compound XXVII exhibits potent analgesia but weak antagonism upon parenteral administration.

The most potent narcotic antagonist, as determined from Table V, is l-3,14 dihydroxy 6 cyclopropylmethylmorphinan (XIXa). The compound is active both orally and parenterally. The normal parenteral dosage range in HO l 1-hydroxy-7-methoxy-1,2,3,4 tetrahydro 2,2 tetramethylene-1-naphthaleneacetonitrile (III).To a stirred solution of 13.8 ml. (0.022 mole) of 1.6 M n-butyl lithium in hexane at -80 C. under nitrogen was rapidly added 13.8 ml. of anhydrous tetrahydrofuran (THF) followed immediately by a solution of 0.82 g. (0.02 mole) of acetonitrile in 20 ml. THF which was added during 7 minutes. After stirring for 1 hour at -80 C., the resulting white suspension was treated during minutes with a solution of 4.60 g. (0.02 mole) of the spiroketone II in 20 ml. THF.

The cold bath was removed and the solution was stirred for minutes before it was poured into ice-water acidified with hydrochloric acid. The layers were separated, and the aqueous layer was extracted with three 25 ml. portions of benzene.

After drying over anhydrous sodium sulfate, evaporation of the solvent and recrystallization of the remaining solid from chloroform, there was obtained 4.4 g. (80%) of white solid III, mp. 140-142 C. The IR and NMR spectra were consistent with the structure.

Anal.Calcd. for C H NO: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.12; H, 7.91; N, 4.89.

Example 3 CH3 0 q 1 (2 aminoethyl)-7-methoxy-1,2,3,4-tetrahydro-2,2- tetramethylene-l-naphthol (IV).T0 a stirred suspension of 0.57 g. (0.015 mole) of lithium aluminum hydride in 20 ml. anhydrous tetrahydrofuran (THF) under N was added a solution of 2.71 g. (0.01 mole) of III in 20 ml. tetrahydrofuran. The reaction mixture was stirred for 4 hours at room temperature (r.t.). It was then cooled and treated with 0.6 ml. of water, followed by 0.6 ml. of 5 N sodium hydroxide and finally 1.8 ml. of water. The inorganic material was filtered off and washed well with ether. The filtrate was extracted with two portions of ml. of 1 N hydrochloric acid. The extract was basified with aqueous ammonia, and the free base was taken up in ether. After drying over anhydrous sodium sulfate and evaporation of the solvent, there was obtained 2.2 g. of slightly yellow oil IV. It was converted to the oxalate salt in acetone and recrystallized from methanol. This procedure yielded 2.9 g. (76%) of white solid, containing 1 mole of methanol of crystallization; m.p. 178-80 C.

In another experiment IV was obtained from II without isolation of III as follows:

4.6 g. (0.02 mole) of the spiroketone II in ml. of tetrahydrofuran was converted to the nitrile III according to the procedure described above. To the resulting cold solution (80 C.) of III, was added 1.14 g. (0.03 mole) of lithium aluminum hydride in small portions. After the addition had been completed, the reaction mixture was stirred at r.t. for 4 hours. After work up as above, there was obtained 5.7 g. overall) of the oxalate salt of IV, m.p. 179-80 C. In both procedures, the IR and NMR spectra were consistent with the desired product.

Anal.Calcd. for C H NO -C H O -CH OH: C, 63.31; H, 7.70; N, 3.69. Found: C, 63.41; H, 7.43; N, 3.79.

Example 4 4a (2 aminoethyl) l,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (V).Method A: Compound IV [1.50 g. (000548)] free base liberated from 2 g. of oxalate salt) in 5 ml. of ether was treated with 1.5 ml. of concentrated HCl under N at 55 -60 C. for 5 hours. To the cooled mixture were added in succession 10 ml. of ether and 10 ml. of water. After shaking, the two layers were separated. The acidic layer was made alkaline with aqueous ammonia and extracted with ether. The ether layer was dried (K CO and concentrated to yield 1.30 g. of pale yellow oil V. It was converted to an oxalate salt in acetone. The crystals were filtered and washed with a small amount of methylene chloride. The IR and NMR spectra were consistent with the structure.

Yield 1.7 g. (96%) of white solid, m.p. 187-89" C.

Anal.-Calcd. for C I-I NO-C H O C, 65.69; H, 7.25; N, 4.03. Found: C, 64.44; H, 7.47; N, 4.43.

Method B: 120 g. of the oxalate salt of IV was slurried in 700 ml. of water, and to it was added 400 ml. of benzene and 60 ml. of concentrated ammonia. The mixture was stirred until all the solid had disappeared (ca. 15 minutes) and then layers were separated. The water layer was extracted with another 100 ml. of benzene, and the combined benzene layers were shaken with 200 ml. of satuated NaCl solution, filtered over K CO and concentrated in vacuo. The residual oil (ca. g.) was dissolved in 300 ml. of ether in a one 1. round bottom flask and while cooling with an ice-water bath and swirling, to it was added carefully 90 ml. of concentrated HCl and then gently refluxed on the steambath for three hours in a closed system using an oil bubbler. Then the layers were separated, and to the water layer was added 150 ml. of water. After cooling, the solid was filtered off and washed with 50 ml. of acetonitrile to yield 80-85 g. of the HCl salt. From the mother liquor a further crop of the product can be obtained by liberating the free base and repeating HCl treatment as above. The product was recrystallized as the hydrochloride from methanol-ether; mp. 135 (dec.).

Anal.-Calcd. for C H NO-HCl-CH OH: C, 66.34; H, 8.66; N, 4.29. Found: C, 66.34; H, 8.02; N, 4.46.

Example 5 W NHCO2Et 0H, 0

4a [2 (ethoxycarbonylamino)-ethyl] l,2,3,4,4a,9- hexahydro 6-methoxyphenanthrene(VI).--To a stirred solution of 51.4 g. (0.2 mole) of amine V and 19.75 g. (0.25 mole) of pyridine in 200 ml. of methylene chloride was added dropwise 27.125 g. (0.25 mole) of ethyl chloroformate at ice-water bath temperature (5-10" C.). After stirring for 10 minutes, the solution was extracted with ml. dilute hydrochloric acid, followed by 100 ml. of water. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated to give an oil which was dissolved in an ether-petroleum ether mixture and filtered through a Celite-charcoal mixture to yield a pale yellow oil in quantitative yield (65.8 g.). The IR and NMR spectra were consistent with the structure.

AnaL-Calcd. for C20H27NO3Z C, 72.9; H, 8.26; N, 4.25. Found: C, 72.71; H, 8.27; N, 4.25.

Example 6 NHCOzElJ CH: O

10,10a a epoxy 4a [2 (ethoxycarbonylamino)- ethyl] 1,2,3,4,4a,9,10,10a octahydro 6 methoxyphenanthrene (VII) .-To a stirred and cooled (-10" C.) solution of 65.8 g. (0.2 mole) of VI in 150 ml. of methylene chloride was added in small portions 25 g. (0.22 mole) of 85% m-chloroperbenzoic acid. The resulting mixture was allowed to stand at room temperature during five hours. After filtration, the filtrate was washed with a 10% sodium sulfite solution until a test for peroxides, with iodine-starch paper, was negative. The solution was then washed with a 5% aqueous sodium bicarbonate solution and finally with water and a saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the methylene chloride solution was evaporated in vacuo. The residual yellow oil was taken up in ether and the resulting solution was diluted with petroleum ether. The cloudy mixture was filtered through a Celite-charcoal mixture and evaporated to dryness to give an oil; weight 65.8 g. (95.4%). The IR and NMR spectra were consistent with the structure.

AnaL-Calcd. for CH27NO4I C, 69.50; H, 7.88; N, 4.05. Found: C, 70.10; H, 7.97; N, 3.97.

Example 7 N-CO Et EH 0.

N ethoxycarbonyl 14 hydroxy 3 methoxyisomorphinan (VIII).-The following reaction was carried out under a nitrogen atmosphere. To a stirred and refluxing suspension of 1.76 g. (73.34 mmole) of sodium hydride in 200 ml. of dry benzene was added a solution of 5.87 g. (66.67 mmole) of dry t-amyl alcohol in 50 ml. of dry benzene. When the hydrogen evolution had subsided (ca. 15 minutes) a solution of 23.0 g. (66.67 mmole) of the epoxide VII in 500 ml. of dry benzene was added dropwise during 4 hours. After the addition had been completed, the reaction mixture was stirred and refluxed for 18 hours. After cooling, 400 ml. of ice water were added and the benzene layer was washed with water and then with a saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation at reduced pressure, the residual oil was dissolved in ether and the resulting solution was diluted with petroleum ether. The cloudy solution was filtered through a Celite-charcoal mixture and evaporated to give 20.0 g. (87%) of a yellow oil. A sample distilled at 160 C./0.05 mm. pressure yielded and oil which solidified upon standing; m.p. 50 C. The IR and NMR spectra were consistent with the structure.

20 Anal.Calcd. for C H NO C, 69.54; H, 7.88; N, 4.05. Found: C, 69.21; H, 8.01; N, 3.95.

Example 8 N CH5 14 hydroxy 3 methoxy N methylisomorphinan (IX).T0 a suspension of 0.38 g. (0.010 mole) of lithium aluminum hydride (LAH) in 10 ml. of anhydrous ether was added dropwise under N a solution of 3.45 g. (0.01 mole) of VIII in 20 ml. ether. The reaction mixture was heated under reflux for 1 hour, cooled and treated with 0.4 ml. of water, 0.4 ml. of 5 N sodium hydroxide and 1.2 ml. water. After filtration, the resulting solid was washed well with ether. The filtrate was evaporated to dryness yielding an oil (2.80 g.) which was converted to its hydrochloride salt and recrystallized from methanol. There was obtained 2.30 g. (71%) of white solid, m.p. 25052 C. (d.).

This product is identical in every respect to the one obtained by another route, i.e.:

Cl-l Kg C03 N- 0001 a o-Eton Ch t) Example 9 N-ethoxycarbonyl-3-meth0xy-A -morphinan (X).To a cooled and stirred solution of 48.0 g. (0.139 mole) of crude VIII in 96 ml. of dry pyridine was added dropwise 48 ml. of POCl under N The reaction mixture was left at room temperature for 7 days, diluted with 200 ml. of benzene, and then carefully poured into ice-Water. The water layer was extracted with 100 ml. of benzene. The combined benzene extracts were Washed with saturated NaCl solution, and then dried over anhydrous sodium sulfate. The removal of the solvent yielded a brown oil which was dissolved in ether. The resulting solution was first diluted with petroleum ether (b.p. 30-60 C.) until it became turbid, and then filtered through a Celite-charcoal mixture. Evaporation of the solvent yielded 36.0 g. (79%) of a colorless oil. The IR and NMR were consistent with the structure.

Anal.Calcd. for C H NO C, 73.37; H, 7.70; N, 4.28. Found: C, 73.22; H, 8.33; N, 4.12.

Example 10 21 yield 5.64 g. of a mixture of u and (XII) epoxides. The IR and NMR spectra were consistent with the structure. A sample distilled at 145 C./0.05 mm. was analysed.

Anal.Calcd. for C H NO C, 69.95; H, 7.34; N, 4.08. Found: C, 69.39; H, 7.35; N, 4.05.

Example 11 N-ethoxycarbonyl-14-hydroxy 3 methoxymorphinan (XIII).-To a solution of 2.5 g. (0.00728 mole) of the mixture of XI and XII epoxides in 100 ml. of anhydrous ethanol was added 0.76 g. (0.02 mole) of sodium borohydride. The mixture was refluxed during 3 hours after which time additional portions (0.38 g.) of sodium borohydride were added every hour during 7 hours. The reaction mixture was cooled, acidified with dilute hydrochloric acid and extracted with methylene chloride. The dried solution (MgSO was evaporated yielding 2.3 g. of an oil.

Thin layer chromatography (TLC) analysis (A1 0 CHCl revealed four components which the following Rf values 0.2, 0.3, 0.5 and 0.6. The first spot was identified as the isomorphinan VIII, while the third spot is some unreacted starting material. The crude oil in chloroform was chromatographed through an alumina column (200 g.). After concentration of the eluate, the remaining oil was recrystallized from an ether-petroleum ether mixture. There was thus obtained 1.27 g. of a white solid (mainly second fraction on TLC) which after two recrystalliza tions from isopropanol melted at l39-40 C. The IR and NMR spectra were consistent with the structure.

Anal.Calcd. for C20H27NO4: C, 69.54; H, 7.88; N, 4.05. Found: C, 69.9; H, 7.99; N, 4.02.

Example 12 14 hydroxy-3-methoxy-N-rnethylmorphinan (XIV).- To a stirred suspension of 0.17 g. (0.0045 mole) of lithium aluminum hydride in ml. anhydrous tetrahydrofuran was added, under N a solution of 0.518 g. (0.0015 mole) of XIII in 10 ml. tetrahydrofuran. The reaction mixture was heated under reflux for 18 hours. Work-up in the usual manner atforded 330 mg. of an oil which was crystallized from petroleum ether. Recrystallization from methanol afforded an analytical sample melting at 113- 15 C. The IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C H NO C, 75.23; H, 8.77; N, 4.87. Found: C, 75.26; H, 8.76; N, 4.68.

Example 13 3,14-dihydoxy-N-methylmorphinan (XV).700 mg. of XIV and 7 ml. of 48% HBr were refluxed under N for 15 minutes. The reaction mixture was cooled, diluted with a small amount of ice Water, made basic with aqueous ammonia and extracted with CHC13. The CHCl extracts were dried (MgSO and evaporated to dryness. The residue was taken up in ether and filtered through Celite-charcoal. The filtrate crystallized. It was filtered to 22 give 400 mg. of a solid which was recrystallized from MeOH to give a white solid, 330 mg., mp. 206-8 C. The IR and NMR spectra were consistent with the structure. Anal.-Calcd. for C H NO C, 74.69; H, 8.48; N, 5.12. Found: C, 74.82; H, 8.58; N, 4.97.

Example 14 3-methoxy-A -morphinan (XI).--A mixture of 32.7 g. (0.1 mole) of crude X, ml. of n-octanol and 28.0 g. KOH pellets was refluxed under nitrogen for 45 minutes. After cooling, the mixture was treated with water and ether (600 ml.). The water layer was discarded, and the organic layer was extracted with 300 ml. of 2 N HCl and 2X 300 ml. of water. The combined aqueous extracts were basified with aqueous ammonia and the free base was taken up in ether, to yield 20 g. of the crude product after drying over K CO and evaporation. The product was converted to an oxalate salt in anhydrous ether. The resulting salt was recrystallized from an acetone-methanol mixture to yield 12 g. (34.8%), m.p. 82 C. Recrystallization from a methanolacetone mixture afforded a sample melting at 187189 C. The IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C H NO-C H O C, 66.07; H, 6.71; N, 4.06. Found: C, 66.28; H, 6.72; N, 4.11.

Example 15 N-cyclopropylcarbonyl 3 methoxy-A -morphinan (XVI).-The acid chloride of cyclopropylcarboxylic acid (3.0 g., 28.7 mmole) was added to a cooled and stirred solution of 6.4 (25 mmole) of XI and 2.5 g. (31.3 mmole) of pyridine in 30 ml. of methylene chloride over a period of 10 minutes. After stirring for another 10 minutes, the solution was washed successively with water, 15 ml. of 0.2 .N NaOH, 10 ml. of 1 N HCl, and again with water. After drying over Na SO the solvent was evaporated, and the residue crystallized from 15 ml. of ether. A total of 7.73 g. (95.7%); m.p. 125-28 C., was obtained. Recrystallization from methanol increased the m.p. to 133-35 C. The IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C H NO C, 77.98; H, 7.79; N, 4.33. Found: C, 77.86; H, 7.87; N, 4.30.

Example 16 N-cyclo pro pylcarbonyl-S 14-ep oxy- 3 -methoxymorphinan (XVII).To a solution of 3.33 g. (10.3 mmole) of XVI in 35 ml. CH CI at 0 C. was added 2.31 g. of 85% m-chloroperbenzoic acid (11.3 mmole). The mixture was stirred at 0-5 C. until all the peracid was dissolved. The mixture was left at room temperature for 6 hours. Work up in usual manner afforded an oil which was dissolved in 10 ml. of ether and left for 24 hours at 5 C. The

solid was filtered off to yield 2.3 g. (66%); m.p. 134- 36' C.

Recrystallization from a CH Cl -ether mixture afforded a sample melting at 140-42 C. the IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C H NO C, 74.31; H, 7.42; N, 4.13. Found: C, 74.13; H, 7.39; N, 4.13.

Example 17 C130 OH N cyclopropylmethyl 14 hydroxy 3 methoxymorphinan (XVIII).T stirred suspension of 1.8 g. of LiAlH in 50 ml. of anhydrous THF was added dropwise during 5 minutes a solution of 6.0 g. (17 mmole) of XVII in ml. THF. The mixture was refluxed during one hour and then worked up in the usual manner. The product was dissolved in petroleum ether (b.p. 40-60 C.) and filtered through Celite-charcoal to give 5.73 g. of an oil. Treatment with anhydrous HCl in ether afforded 6.15 g. (95.5%) of the hydrochloride salt, m.p. 223-25 C. Recrystallization from methanol-ether increased the m.p. to 259-60 C. The IR and NMR spectra were consistent with the structure.

AnaL-Calcd. for C H NO -HCl-' /2H O: C, 67.67; H, 8.37; N, 3.76. Found: C, 67.70; H, 8.02; N, 3.72.

Example 18 3,14 dihydroxy N cyclopropylmethylmorphinan (XIX).-Method A: A mixture of 4.1 g. (11.7 mmole) of the hydrochloride salt of XVIII and 13.4 g. of anhydrous pyridine hydrochloride was heated under nitrogen at 187-95 C. for 1 hour. The cooled mixture was dissolved in 40 ml. of water, basified with aqueous ammonia and extracted with 2x 40 ml. of ether. Drying and evaporation of the solvent yielded 3.0 g. of semi-solid product, which was dissolved in ether. After treatment with charcoal, the product crystallized to yield 2.54 g. (69.4%) of free base, m.p. 157-59 C. The hydrochloride salt, recrystallized from methanol-acetone, had a m.p. 17981 C. with contraction starting at 163. The product analysed for /2 molecule of methanol of crystallization. The IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C H NO -HCl- /2CH OI-I: C, 67.32; H, 8.37; N, 3183. Found: C, 67.56; H, 8.20; N, 3.90.

Method B: Into a cooled (Dry Ice-acetone) three 1. three-necked flask equipped with a mechanical stirrer, dropping funnel and a gas trap was placed a solution of 133.1 g. (0.5312 mole) of BBr in 250 ml. of dry methylene chloride. Then a solution of 58 g. (0.0177 mole) of the free base XVIII in 1.2 l. of dry methylene chloride was added dropwise under nitrogen (time=1 hour).

After the addition had been completed, the reaction mixture was stirred in the cold for one hour, and then at room temperature for three hours. (1) The reaction mixture was cooled (ice-bath) and carefully decomposed with 350 ml. of cold water. (2) It Was transferred into a four I. Erlenmeyer flask and treated carefully with 200 ml. of concentrated ammonium hydroxide with cooling and stirring. The layers were separated and the aqueous layer extracted with 200 ml. of methylene chloride. The combined organic extracts were dried (MgSO and evaporated, in vacuo, to give an oil in quantitative yield.

The oil was taken up in 250 ml. of reagent acetone,

cooled, and treated with 17 ml., of concentrated hydrochloric acid. After standing in the cold for 18 hours, the solid was collected by filtration and washed with 2X 60 ml. of cold acetone. The product was recrystallized from 90% ethyl alcohol. The IR and NMR spectra were consistent with the structure.

Yield: 55.0 g. (86.3%); m.p. 275-77 C. (dec.).

Anal.--Calcd. for C H NO -HCl: C, 68.65; H, 8.07; N, 4.00. Found: C, 68.01; H, 8.17; N, 3.88.

(1) During one hour at 70 C. the boron complex hardened and stirring was very dilficult. The cold bath was removed and the stirring resumed after softening of the mass. The reaction mixture was then stirred during three hours at room temperature.

(2) During the initial stage of decomposition, a violent reaction might occur. Therefore, it was essential to provide vigorous stirring and etficient cooling during the slow addition of water.

Example 19 CHO 3-methoxy-N-trifiuoroacetyl-A morphinan (XX). To a solution of 5.1 g. (20 mmole) of the secondary amine XI in 60 ml. of dry ether was added 24 g. (280 mmole) of Na CO The mixture was cooled and vigorously stirred, and 32 ml. (228 mmole) of trifiuoroacetic anhydride was added at as rapid a rate as possible without the reaction getting out of control. The cooling bath was removed and the vigorous stirring continued for 20 minutes. The reaction mixture was poured into chloroform, the excess anhydride was destroyed with ice, and the chloroform, the excess anhydride water, dried and evaporated to give an oil; weight 6.33 g. The oil was covered with 15 ml. of ether and it crystallized on standing. It was filtered to give a solid 4.96 g. (70%), m.p. 94-96%. The IR and NMR were consistent with the structure.

AnaI.-Calcd. for C H NO C, 64.95; H, 5.74; N, 3.99. Found: C, 65.34; H, 6.76; N, 3.03.

Example 20 8,14-ep0xy-3-methoxy N trifluoroacetylmorphinan (XXI).-The procedure is the same as that described for the preparation of compound VII in Example 6 using the following materials 23.85 (10.96 mmole) of compound XX; 2.07 g. (12 mmole) of m-chloroperbenzoic acid; and 30 ml. of methylene chloride. Reaction time, 6 hours.

After the usual work up the residual oil was covered with 5 ml. of ether. Crystals formed which were collected by filtration. An analytical sample was prepared by recrystallization from methanol; m.p. 102-5 yield: 3.35 g. (82.6%). The IR and NMR spectra were consistent with the structure.

Anal.Calcd. for C H F NO C, 62.12; H, 5.49; N, 3.82. Found: C, 62.07; H, 5.38; N, 3.73.

25 Example 21 Example 22 l4-hydroxy-3-methoxymorphinan (XXIII).A solution of 800 mg. of the amine-epoxide (XXII) in ml. of tetrahydrofuran was added dropwise at room temperature, to a suspension of 500 mg. of lithium aluminum hydride in 5 ml. of dry tetrahydrofuran. After the addition had been completed the reaction mixture was stirred and refluxed during fifteen minutes. Work-up as usual yielded 700 mg. of an oil which was dissolved in ether and the resulting solution was filtered through a Celite-charcoal mixture. The filtrate was treated with a saturated solution of hydrochloric acid in ether to yield 720 mg. of a white hydrochloride salt which after recrystallization from methanol melted at 243-44 C. (dec.). The IR and NMR were consistent with the structure.

AnaL-Calcd. for C H N0 'HCl-%CH OH: C, 64.50; H, 8.04; N, 4.30. Found: C, 64.18; H, 7.81; N, 4.25.

Example 23 3,14-dihydroxy-morphinan (XXIV).-A mixture of 140 mg. (0.5 mmole) of XXIII and 0.55 g. of pyridine hydrochloride was heated under N, at 185-95 C. for 1 hour. The mixture was cooled, treated with water and NH OI-I and extracted with CHCl The CHCI extracts were dried and evaporated to give a solid 53.6 mg. This was treated wtih ether and filtered. The solid was recrystallized from MeOH to give mg./m.p. 264- 66 C. (d.). The IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C H NO C, 74.1; H, 8.16; N, 5.40. Found: C, 73.84; H, 8.35; N, 5.33.

Example 24 N-cyclobutylcarbonyl l4 hydroxy 3 methoxymorphinan (XXV).T0 a stirred and cooled solution of 400 mg. (0.00146 mole) of the amino alcohol XXIII in 0.16 g. (0.002 mole) of dry pyridine and 5 ml. of methylene chloride, there was added, dropwise, a solution of 0.19 g. (0.0016 mole) of the acid chloride of cyclobutyl carboxylic acid in 5 ml. of methylene chloride. After stirring for ten minutes the reaction mixture was washed Successively with cold dilute aqueous hydrochloric acid, dilute aqueous sodium hydroxide, water and finally with a saturated aqueous sodium chloride solution. After drying over Na SO and evaporation of the solvent, there was obtained 400 mg. of an oil which crystallized on standing. The oil was treated with a small amount of cold ether and filtered to yield 320 mg. (61.6%) of crystals which after recrystallization from methanol melted at 183-85 C. The IR and NMR spectra were consistent with the structure.

Anal.Calcd. for C H NO C, 74.33; H, 8.22; N, 3.94. Found: C, 74.19; H, 8.40; N, 3.75.

Example 25 N cyclobutylmethyl 14 hydroxy 3 methoxymorphinan (XXVI).T0 a suspension of 1.0 g. of lithium aluminum hydride in 5 ml. of dry tetrahydrofuran was added at room temperature, under an atmosphere of nitrogen, a solution of 2.14 g. (6 mmole) of the amide XXV in 25 ml. of tetrahydrofuran. The reaction mixture was then refluxed during thirty minutes and worked up as usual to yield 2.0 g. of an oil which was dissolved in ether and the resulting solution filtered through a Celitecharcoal mixture.

Treatment with dry HCl gas yielded 2.04 g. of the hydrochloride; m.p. 235-37" C. (dec.). Recrystallization from methanol increased the melting point to 248-50 C. (dec.). The IR and NMR spectra were consistent with the structure.

Anal.Calcd. for C H N0 -HCl- /zH O: C, 68.28; H, 8.60; N, 3.62. Found: C, 68.25; H, 8.40; N, 3.75.

Example 26 N cyclobutylmethyl 3,14 dihydroxymorphinan (XXVII).A mixture of 1.0 g. (2.58 mmole) of XXVI and 10 ml. of 48% HBr was refluxed, under a nitrogen atmosphere, during five minutes. After cooling, the reaction mixture was diluted with water and made basic with aqueous ammonium hydroxide. The aqueous basic mixture was extracted with chloroform and the combined chloroform extracts were dried over anhydrous sodium sulfate. After evaporation of the solvent, the residual oil (730 mg.) was taken up in dry ether and the resulting solution filtered through Celite-charcoal. The filtrate was treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained was collected by filtration and recrystallized from a methanolacetone mixture to yield 565 mg. (56.5 %')of crystals melting at 272-74 C. (dec.). The IR and NMR spectra were consistent with the structure.

Anal.-Calcd. for C21H29NO2 /2 CHgOH: C, 67.97; H, 8.49; N, 3.49. Found: C, 68.10; H, 8.14; N, 3.80.

27 Example 27 N-allyl-l4-hydroxy-3-methoxymorphinan (XXVIII). To a stirred mixture of 900 mg. (3.3 mmole) of the aminoalcohol XXIII and 1.7 g. (16.5 mmole) of triethylamine in 12 ml. of absolute ethanol was added, at room temperature and under nitrogen, a solution of 0.605 g. mmole) of allyl bromide. After the addition had been completed the reaction mixture was refluxed for eighteen hours and then evaporated to dryness. The residue was mixed 'with a aqueous sodium carbonate solution and the resulting mixture extracted with several portions of ether. The combined ether extracts were dried over Na SO and evaporated to yield 940 mg. of an oil which was dissolved in ether. The resulting solution was filtered through a Celite-charcoal mixture and the filtrate concentrated at reduced pressure. The remaining oil was converted, in ether, into the hydrochloride salt. Recrystallization from a methanol-ether mixture yielded 600 mg. of a white solid melting at 244-46 C. (dec.). Yield, 51.9%. The IR and NMR spectra were consistent with the structure.

AnaI.Calcd. for C H NO 'HCl: C, 68.65; H, 8.07; N, 4.00. Found: C, 68.01; H, 7.97; N, 3.90.

Example 28 N-allyl-3,l4-dihydroxymorphinan (XXIX).--To a solution of 3.814 g. (12.135 mmole) of XXVIII in 90 ml. of dry CH Cl at -80 C. was added under N dropwise a solution of 9.4252 g. (37.42 mmole) of BBr of 20 ml. of dry CH Cl The resulting reaction mixture was allowed to Warm up to room temperature slowly for 18 hours. It was decomposed with ice-water and the layers separated, the CH CI solution washed with water and saturated NaCl solution. It was dried and evaporated to give 3.76 g. of an oil. This was converted to its HCl salt in acetone. The HCl salt obtained was recrystallized from water-acetone to give 1.15 g. of a white solid. The mother liquor was concentrated and converted to its free base. The free base was chromatographed on A1 0 (Act. 4) and eluted with CHCI to give a fraction (1.35 g.) which was converted to its HCl salt. The HCl salt was recrystallized from H O-acetone to give 950 mg. The IR and NMR were consistent with the structure.

Total yield 2.10 g. (50% Anal.-Calcd. for C H NO -HCl- /2CH OH: C, 66.56; H, 8.02; N, 3.98. Found: C, 66.65; H, 7.76; N, 3.88.

Example 29 N-dimethylallyl 14 hydroxy 3 methoxymorphinan (XXX).Substitution in the procedure of Example 27 for the allyl bromide used therein of an equimolar quantity of dimethylallyl bromide produces the title compound.

28 Example 30 -CH= N CH C N-dimethylallyl-3,l4-dihydroxym0rphinan (XXXI) Substitution in the procedure of Example 28 for the compound XXVIII used therein of an equimolar quantity of compound XXX produces the title compound.

Example 31 N-2'-methylallyl 14 hydroxy 3 methoxymorphinan (XXXIIyfiSubstitution in the procedure of 'Example 27 for the allyl bromide used therein of an equimolar quantity of Z-methylallyl bromide produces the title com- (XXXIII).-Substitution in the procedure of Example 28 for the compound XXVIII used therein of an equimolar quantity of compound XXXII produces the title compound.

Example 33 N cyclopropylmethyl-3-acetoxy-l4-hydroxymorphinan (XXXIV).-Equimolar quantities of acetyl chloride, compound XIX and pyridine are mixed together in dry methylene chloride and the resultant mixture is heated to 60 C. for several hours under a nitrogen atmosphere to produce the title compound.

Example 34 o wa 1 II on N 0,-0 "N N-cyclopropylmethyl 3 nicotinoyloxy-14-hydroxymorphinan (XXXV).Equimolar quantities of nicotinoyl chloride hydrochloride, compound XIX and pyridine are mixed together in dry methylene chloride and the mixture is heated to 50 C. for 3 hours to produce the title compound.

Example 35 OH CH O-CH -O u.

N-cyclobutylmethyl-14-hydroxy 3 methoxymethyloxymorphinan (XXXVI).One mole of compound XXVII was placed in 3 liters of benzene. One mole of sodium methoxide was added, followed by the slow addition of 1 mole of chloromethyl ether with stirring. The solution was heated to reflux to yield the title product.

Example 36 ..cg o o-ti-cn N cyclobutylmethyl 3,14 diacetoxymorphinan (XXXVII).-Two moles each of acetic anhydride and pyridine are mixed with one mole of compound XXVII in dry methylene chloride. The solution is heated to reflux for 24 hours under nitrogen to produce the title compound.

Example 37 Example 38 Resolution of dl-3,14-dihydroxy-N-cyclopropylmethylmorphinan into its d and 1 optical isomers.(A) l-3,14- dihydroxy-N-cyclopropylmethylmorphinan (XIXa): dl- 3,14 dihydroxy-N-cyclopropylmethylmorphinan (7.835 g., 25 mmole) as the free base was dissolved in 15 ml. of hot methanol. To this was added a solution of 3.75 g. (25 mmole) of l-tartaric acid in 15 ml. of hot methanol. The resulting solution was diluted with 30 ml. of acetone and let stand at 5 C. for 60 hours to crystallize. It was filtered to yield 3.2 g. of a crystalline solid (A). The mother liquor was evaporated to dryness and was made basic with aqueous ammonia to give approximately 5.0 g. of free base (B).

The solid (A) was recrystallized nine times from methanol-acetone to give 500 mg. of the tartrate salt; [a] =--63.2375 (C., 0.4; MeOH).

The free base was liberated with ammonia and recrystallized from CH Cl mp. 178-180 C., weight 300 mg; e] =-91.26 (0., 0.4408; CHCl This is 1- isomer (XlXa).

(B d-3, l4-dihydroxy-N-cyclopropylmethylmorphinan (XIXb): The free base (B), 5.0 g., obtained in step (A) above, was dissolved in hot methanol and an equivalent amount of d-tartaric acid dissolved in hot methanol was added. This yielded 5.0 g. of tartrate salt which was recrystallized seven times from methanol acetone; [u] |-63.679 (C., 0.4028, MeOH).

The tartrate salt was liberated as its free base and recrystallized from CI-lCl m.p. 178-179 C.; weight 650 mg; [oc]; ='+91.83 C. (0., 0.4168, CHCl This is the d-isomer (XIXb).

Example 39 Resolution of the compounds of the instant invention into their respective optical isomers-Substitution into the general procedure of Example 38 for the dl-3,14-dihydroxy-N-cyclopropylmethylmorphinan used therein of an equimolar quantity of a dl-3,l4-dihydroxy-N-substituted-morphinan will produce the resolved d and l isomers. Example 40 1 3,14 dihydroxy N-cyclopropylmethyhnorphinan pamoate.1 3,14 dihydroxy-N-cyclopropylmethylmorphinan (0.1 mole) is dissolved in hot methanol. A solution of 0.1 mole of pamoic acid dissolved in hot nitrobenzene is added to the first solution with vigorous agitation. The product that crystallizes is the pamoate salt of XIXa.

Example 41 Salt preparation of the compounds of the instant invention.-Substitution in the procedure of example 40 for the pamoic acid used therein of an equimolar quantity of sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric, tartaric, lauric, stearic, palmitic, oleic, myristic, lauryl, sulfuric, naphthabenzenesulfonic, linoleic or linolenic acid produces the corresponding acid addition salt of 1-3,l4-dihydroxy-N-cyclopropylmethylmorphinan.

We claim:

1. A compound having the formula XXXX wherein R is selected from the group consisting of in which R is H or CH R is selected from the group consisting of H, (lower)alkyl or 1 to 6 carbon atoms (lower)alkanoyl of 2 to 6 carbon atoms and and R is selected from the group consisting of H and (lower)alkanoyl of 2 to 6 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 having the formula in which R is H or CH R is and R is H or acetyl; or a pharmaceutically acceptable acid addition salt thereof.

31 4. A compound of claim 2 wherein R is is CH: -cmfl -cmor -orn-oH=o R is and R is H; or a pharmaceutically acceptable acid addition salt thereof.

5. The compound of claim 2 wherein R is H, R is and R is H; or a pharmaceutically acceptable acid addition salt thereof.

6. The hydrochloride salt of the compound of claim 5. 7. The compound of claim 2 wherein R is H, R is 12. The levorotatory isomers of the compounds of claim 4.

13. The levorotatory isomer of the compound of claim 5.

14. The levorotatory isomer of the compound of claim 6.

15. The levorotatory isomer of the compound of claim 7.

16. The levorotatory isomer of the compound of claim 8.

References Cited UNITED STATES PATENTS 2,885,401 5/1959 Grussner 260-285 3,166,559 1/1965 Sawa et al. 260-285 3,201,403 8/1965 Sawa et al. 260-285 3,230,224 1/1966 Sawa et al. 260-285 3,285,922 11/1966 Gates et al. 260-285 3,654,280 4/1972 SaWa et al 260-285 OTHER REFERENCES Natl Acad. Sciences, Natl Research Council, Problems of Drug Dependence, p. 5 (1967).

Villarreal et al.: Addendum 1, Comm. on Problems of Drug Dependence, 29th Meeting, pp. 1-12 (1967).

DONALD G. DAUS, Primary Examiner US. Cl; X.R.

260-240 K, 247.5, 348 C, 465 F, NIC, 570.5 CA, 570.8 TC, 586 R; 424-260 

